tbuckley/cabot-search huggingface dataset:
CTNI-55. A MULTICENTER STUDY OF LOW-INTENSITY FOCUSED ULTRASOUND WITH SYSTEMIC MICROBUBBLE OSCILLATORS FOR BLOOD-BRAIN BARRIER DISRUPTION FOR LIQUID BIOPSY IN GLIOBLASTOMA (LIBERATE)
Authors: Manmeet Ahluwalia, Michael McDermott, Terry Burns, John de Groot, Alon Mogilner, Achal Achrol, Bhavya Shah, Chetan Bettegowda, Ahmad Ozair, Atulya Khosla, Theodore Schwartz, Arjun Sahgal, Mark Mishra, Richard Everson, Jeffrey Weinberg, Nduka Amankulor, Justin Sporrer, Christopher Cifarelli, Ali Rezai, Nir Lipsman, Graeme F Woodworth
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Liquid biopsy in glioblastoma (GBM) is hindered by a lack of requisite circulating-free DNA (cfDNA) blood levels in due to the blood-brain barrier (BBB). Real-time image-guided low-intensity focused ultrasound (LIFU) with intravenously administered microbubble oscillators non-invasively causes BBB disruption (BBBD). This clinical trial aimed to evaluate the utility of LIFU for increasing cfDNA in blood for liquid biopsy in GBM. METHODS LIBERATE is an ongoing, prospective, multi-center, self-controlled, ongoing, pivotal trial evaluating the safety and technical efficacy of LIFU for BBBD to increase cfDNA in blood for GBM. Patients aged 18-80 years with suspected GBM planned for tumor biopsy or resection at ten centers in the US are being included. Patients are administered intravenous oscillating microbubbles for enhancing sonication, after which MR-guided BBBD using 220 kHz LIFU device is performed, with real-time acoustic feedback for effective sonication. Pre- and post-procedure, phlebotomies, and MRI brain are performed. The primary study endpoint is defined, per subject, as the ratio between cfDNA levels in blood 1-hour post-LIFU procedure compared to cfDNA level in blood pre-procedure. The primary study hypothesis is that BBBD with LIFU leads to ≥2-fold increase in cfDNA in blood. The secondary hypothesis is that there exists ≥75% concordance between biomarker patterns in the cfDNA sample from 1-hour post-LIFU sample and tumor tissue obtained later. Exploratory endpoints include (1) sensitivity of detection of known somatic mutations in cfDNA from blood samples collected before and after LIFU, (2) estimation of cfDNA levels in samples collected at 30 minutes, 1 hour, 2 hours, and 3 hours post-LIFU to determine the time of greatest yield, (3) correlation of MRI parameters related to BBBD grading and biomarkers in cfDNA from post-LIFU samples. Patient enrollment commenced in 2022, and 13 patients have been recruited by 06/09/2023. Clinical trial information: NCT05383872.
STEM-01. PLEXIN-B2 DRIVES CONFINED MIGRATION OF GLIOBLASTOMA STEM CELLS THROUGH MEMBRANE TENSION, ENDOCYTOSIS, AND MECHANO-ELECTRO REGULATION
Authors: Chrystian Junqueira Alves, Angela Dixon, Theodore Hannah, Robert Wiener, Ha Nguyen, Murray Tipping, Júlia Silva Ladeira, Rodrigo Alves Dias, Priscila Zabala Capriles, José Paulo Rodrigues Furtado de Mendonça, Paul Slesinger, Kevin Costa, Hongyan Zou, Roland Friedel
Journal: Neuro-Oncology (2023)

Abstract Glioblastoma is a malignant brain tumor of uncontrolled proliferation and infiltration. GBM stem cells (GSCs) are constantly challenged by confined spaces during their migration through the brain parenchyma. Understanding the factors that drive GSC confined migration (CM) is thus critical for effective drug development. Using microchannel devices, we showed that GSCs are adept at squeezing through narrow constrictions at faster speed than through non-constricted spaces. During CM, cytoskeletal components and plasma membrane self-organize to establish polarity and propel the cell through the constrictions. Among the mechanical plasticity observed for meeting the challenges of CM the cells remodel their shape and plasma membrane through increased endocytosis. Rapid endocytosis of inner leaflet anionic phospholipids-such as PI(4,5)P2 and phosphatidylserine at the front of the cell collectively contribute to drive positive-charged actin filaments and calcium to the rear end of cells, abruptly leading to localized changes in membrane potential and propelling the cell. Correspondingly, inhibiting endocytosis abrogates polarity and results in failure to CM. These effects were recapitulated by deletion of the cell surface receptor Plexin-B2. Plexin-B2-CRISPR knockout (KO) GSCs displayed reduced capability to squeeze through constrictions in microchannel devices. Mechanistically, Plexin-B2 KO in GSCs compromised membrane dynamics and reduced endocytosis as consequence of low cell stiffness and membrane tension. Computational simulations demonstrated that membrane tension couples with cell stiffness in feedback loops and support the model that Plexin-B2 controls membrane tension through actomyosin contractility. On a molecular level, the locked extracellular ring domain of Plexin-B2 prevents GSCs to migrate through constrictions and recapitulates the defects associated with Plexin-B2 KO phenotype, indicating that ring bending is required for membrane tension. Thus, our results describe critical mechano-electro events necessary to establish polarity and prompt GSCs migration under confinement and provide a mechanism by which a single mechanosensor exert regulation at the cytoskeletal and membrane levels.
INNV-34. A NOVEL APPROACH TO ADDRESSING THE UNIQUE NEEDS OF ADOLESCENT AND YOUNG ADULT (AYA) BRAIN TUMOR PATIENTS: A FRAMEWORK FOR A VIRTUAL PEER-LED YOUNG ADULT SUPPORT GROUP
Authors: Dace Hines, Katie Scotford, Phoebe Bryson-Cahn, Naomi Hoffer, Mary Destri, Alexa Greenstein, Susan Chang, Jessica Schulte
Journal: Neuro-Oncology (2023)

Abstract INTRODUCTION Adolescent and young adult (AYA) patients (age 15-39) constitute 14.3% of new brain tumor diagnoses annually. While navigating cognitive and physical challenges from their tumor, these patients are also pursuing social independence, education, careers, relationships, and family planning. These patients have unique, and often unmet, psychosocial needs compared to older patients, requiring a new approach for comprehensive care. METHODS Three YA neuro-oncology patients from UCSF volunteered to facilitate a monthly virtual support group. Facilitators were trained in peer support mentorship and support group facilitation by a licensed psychologist. A program planning committee consisted of: a social worker, nurse practitioner, program manager, communications specialist, two neuro-oncologists, and the peer facilitators. Promotion was done through flyers, the UCSF and ABTA websites, and word-of-mouth. Feedback was collected via anonymous survey and informal discussions, and the planning committee met monthly to adapt to evolving group needs. Participants used a video chat app to stay connected between meetings. RESULTS Over one year, 73 patients registered, and 40 total participated (average 15/session). Participant age range was 19–44, and age at diagnosis was 10–43. From 19 survey responses, 84% preferred a mix of open and topic-driven discussions. Key topics desired for peer discussion included meditation/mindfulness (68%), cognitive changes (58%), symptom management (58%), relationships/sexual health (58%), exercise (58%), and anxiety (58%). By contrast, participants wanted healthcare providers to address tumor treatment (37%), cognitive challenges (37%), symptom management (32%), seizures (26%), nutrition (26%), and integrative health (21%). Qualitative feedback highlighted community and social support from similarly-aged peers facing similar challenges amongst the most valuable aspects. CONCLUSIONS AYA patients have different information and support needs from peers versus providers. Peer-led support groups effectively provide social support for AYA brain tumor patients. Successful implementation involves volunteer facilitators, training, regular planning committee meetings, and participant feedback.
RADT-45. TREATMENT OF ATYPICAL CENTRAL NEUROCYTOMA WITH PROTON THERAPY
Authors: Pawan Singh
Journal: Neuro-Oncology (2023)

Abstract Central neurocytoma is a rare intraventricular tumor often thought to be benign but can demonstrate aggressive behavior such as recurrence or CNS dissemination with elevated MIB1 index. This is a clinical case presentation of a 19 year old male who presented with increased intracranial pressure and was found to have atypical central neurocytoma with Ki-67 of 5%. Given residual disease after second craniotomy and high risk for recurrence, patient was treated with a six week course of proton therapy. Patient responded to radiation therapy with stable disease and improvement of cognitive function. Outcome of disease stability with proton therapy is consistent with reported literature. This case adds further evidence for use of proton therapy in patients with atypical central neurocytoma.
NCOG-31. TUMOR TREATING FIELDS: REAL-WORLD SURVIVAL AND QUALITY OF LIFE OUTCOMES ON THE XCELSIOR PLATFORM
Authors: Joshua Palmer, Fernando Nino de Rivera, Alaa Awawda, Sebastian Williams, Sabrina Irizarry, Zachariah Cole, Gordon Chavez
Journal: Neuro-Oncology (2023)

Abstract OBJECTIVE xCures operates a direct-to-patient, real-world evidence platform according to the nationwide observational research protocol XCELSIOR (NCT03793088), which aggregates medical data in an FDA-compliant electronic database. We used this platform to analyze advanced registry survival and Quality of Life (QoL) outcomes associated with the use of Tumor Treating Fields (TTFields) for treatment of high grade central nervous system (CNS) tumors. METHODS XCELSIOR participants with high grade CNS tumors were invited weekly to complete the EuroQol 5-Dimension (EQ-5D-5L) QoL questionnaire over the course of one year. A EuroQol-endorsed model was used to estimate health state utilities from patients’ EQ-5D responses. The participating patients’ clinical data was accessed from the XCELSIOR platform to enable study of clinical factors and survival outcomes. RESULTS 225 patients with high grade CNS tumors in total completed at least one EQ-5D questionnaire. 88 patients (39%) had ever used TTFields and 58 of these patients (26%) were currently using TTFields. Patients currently using TTFields had significantly higher average health state utility estimates compared to non-users (p=.00183), with a mean improvement in utility of .14 (SE=.04), indicating significantly higher overall QoL in TTFields users. Mortality events were recorded for 40 participating patients, 14 (35%) of which had used TTFields. From these 40 events the mean/median overall survival (OS) for patients who had used TTFields was 23.39/20.15 months vs 15.77/12.72 months for patients who had not used TTFields, showing significantly higher average OS in patients who had used TTFields (p=.04139). CONCLUSION The XCELSIOR platform has enabled the study of real-world clinical and QoL outcomes for patients with CNS tumors. The results show that use of TTFields is associated with improved survival as well as improved overall Quality of Life for patients in a real-world setting, corroborating results seen in trial settings as well as results seen in other real-world studies.
MODL-32. EGFRVIII OVEREXPRESSION AND LOSS OF MOUSE SPECIFIC CDKN2A IN GLIAL CELLS LEADS TO GLIOMAGENESIS IN A NOVEL MOUSE MODEL
Authors: Olivia Singh, Mira Li, Hafsah Ali, Mathew Voisin, Qingxia Wei, Andrew Gao, Sameer Agnihotri, Kelly Burrell, Mark Wilson, Shirin Kamiri, Kenneth Aldape, Gelareh Zadeh
Journal: Neuro-Oncology (2023)

Abstract A new mouse model for the classical subtype of human glioblastoma has been generated using Cre-mediated EGFRvIII overexpression and homozygous p19-ARF deletion (the mouse homolog of human p14-ARF/CDKN2A) in GFAP expressing cells. Transgenic mice develop intraparchenymal and/or leptomeningeal brain lesions with some spinal cord invasion as early as 1 month old and 95% of mice die by 6 months due to hydrocephalus and/or paralysis. Mice with high grade tumors have worse survival and similar features to human classical glioblastoma such as necrosis, high levels of mitosis, and infiltration of tumor cells into normal brain. Immunohistochemical analysis confirms EGFRvIII overexpression and p19-ARF loss in tumor cells, along with patchy positive GFAP and positivity for Olig2, S100β and NeuN, suggesting that tumor cells arise from a progenitor glial cell type. Adherent and neurosphere primary culture of dissociated tumors indicate that tumor cells maintain EGFRvIII expression in culture and are able to generate xenograft tumors by 3 weeks after intracranial injections into NODSCID mice. Xenograft tumors are reminiscent of the primary tumor, with similar histopathological features and immunohistochemical staining. This novel mouse model can be used to study diffuse glioma with a leptomeningeal component.
EXTH-63. MTA-COOPERATIVE PRMT5 INHIBITORS ARE EFFICACIOUS IN MTAP-DELETED MALIGNANT PERIPHERAL NERVE SHEATH TUMOR MODELS
Authors: Dana Borcherding, Xiaochun Zhang, Minjie Zhang, Himanshi Bhatia, Yang Lyu, Kevin He, Liuzhan Yang, Kuangying Yang, Heather DiBenedetto, Alice Tsai, Alan Huang, John Maxwell, Kevin Cottrell, Kimberly Briggs, Angela Hirbe
Journal: Neuro-Oncology (2023)

Abstract OBJECTIVES Malignant peripheral nerve sheath tumors (MPNST) are highly aggressive sarcomas with limited treatment options and poor survival rates, necessitating the development of novel therapeutics. Approximately 25-50% of MPNST harbor loss of the enzyme methylthioadenosine phosphorylase (MTAP) due to a passenger deletion driven by loss of the proximal tumor suppressor gene, CDKN2A. PRMT5 was identified as a selective dependence in MTAP-deleted cells due to the accumulation of the substrate methylthioadenosine (MTA), which is itself an endogenous PRMT5 inhibitor. TNG908 and TNG462 are clinical stage MTA-cooperative PRMT5 inhibitors that demonstrate selectivity for MTAP-deleted cells over MTAP-intact cells of 15X and 45X, respectively. Previous reports show both molecules drive durable tumor regressions in xenograft models of various MTAP-deleted cancer histologies. Here, our objectives are to examine the activity of TNG908 and TNG462 in preclinical MPNST models. METHODS The proliferation effects of MTA-cooperative PRMT5 inhibitors, TNG908 or TNG462, and a SAM-cooperative PRMT5 inhibitor, GSK3326595, on MTAP-deleted and MTAP-intact MPNST cell lines were determined using CellTiter-Glo (CTG) assays. TNG908 and TNG462 were further profiled in two MTAP-deleted MPNST patient-derived xenograft (PDX) models, WU-356 and WU-386. RESULTS Incubation with the MTA-cooperative PRMT5 inhibitors, TNG908 and TNG462, selectively decreased the proliferation of MTAP-deleted MPNST cell lines relative to MTAP-intact MPNST cell lines. TNG908 and TNG462 drove dose-dependent antitumor activity including tumor regressions in the MTAP-deleted MPNST PDX models, WU-356 and WU-386, at well-tolerated doses. CONCLUSIONS The clinical stage MTA-cooperative PRMT5 inhibitors TNG908 (NCT05275478) and TNG462 (NCT05732831) are efficacious in MPNST models in vitro and in vivo and are therefore promising therapeutic agents for patients with MTAP-deleted MPNST.
QLTI-07. DOSE-EFFECT RELATIONSHIP OF DEXAMETHASONE ON OUTCOMES OF BRAIN METASTASES
Authors: Lauren Webb, Jessica White, Bryan Neth, Ugur Sener, Rafid Mustafa
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Dexamethasone is commonly used to manage peritumoral edema and alleviate neurologic symptoms in patients with intracranial tumors. The optimal dexamethasone dose for brain metastases is unknown and widely variable. Recent literature reports the most common regimen is 4 mg four times daily. However, the half-life of dexamethasone is 35-54 hours, suggesting that such frequent dosing may be unnecessary. We explored the dose-effect relationship of dexamethasone on brain metastases patient outcomes to improve quality of care. METHODS We retrospectively identified 100 patients (1/1/2016 – 12/31/2022) with brain metastases who were treated with dexamethasone and had adequate follow-up. All patients received standard oncologic care including chemotherapy, radiotherapy, and/or surgical intervention. We evaluated the association between dexamethasone dosing regimens (&amp;lt; 4 mg twice daily versus &amp;gt; 4 mg three times daily), clinical outcomes (performance status, clinical and radiographic response to corticosteroids, survival), and dexamethasone adverse effects during the acute presentation and at first neuro-oncologic follow-up. RESULTS Seventy-two patients received less frequent dexamethasone dosing (&amp;lt; 4 mg twice daily), while 28 received more frequent dexamethasone dosing (&amp;gt; 4 mg three times daily). Patients with higher frequency dexamethasone dosing were more likely to have radiographic evidence of midline shift (p &amp;lt; 0.001), compression of ventricles (p &amp;lt; 0.001), and herniation (p = 0.0020) at presentation. Those with more frequent dosing more often demonstrated radiographic response to dexamethasone (67.9% vs. 45.8%, p = 0.0323), but there were no differences in symptomatic improvement, Karnofsky Performance Status, seizure reduction, survival, or the frequency of adverse events (e.g., hyperglycemia, hypertension, infection, psychosis) between the two cohorts. CONCLUSIONS These results suggest that for most patients with brain metastases, less frequent dexamethasone dosing may lead to clinical outcomes that are similar to those patients who received more frequent dosing. However, higher doses of dexamethasone can be considered for those with more concerning radiologic features.
MODL-31. USING GENETICALLY-ENGINEERED MOUSE MODELS OF TREATMENT-NAÏVE AND -EXPERIENCED NTRK FUSION-DRIVEN GLIOMAS FOR PRE-CLINICAL TRIALS OF TYROSINE KINASE INHIBITORS
Authors: Sebastian Schmid, Zachary R Russell, Madeline West, Julia Walker, Eric Holland, Frank Szulzewsky
Journal: Neuro-Oncology (2023)

Abstract Gene fusions that contain the kinase domain of the three neurotrophic tyrosine kinase receptor (NTRK) genes are frequently observed in infantile high and low-grade gliomas. While these tumors initially respond to treatment with NTRK tyrosine kinase inhibitors (TKIs), treatment resistance and recurrence eventually occur. Treatment-resistant tumors frequently harbor either on-target (in the fusion's kinase domain) or off-target mutations (in downstream effectors of mitogen-activated signaling pathways). Therefore, overcoming this resistance requires a three-pronged strategy: 1) identifying new kinase inhibitors capable of targeting NTRK fusions with on-target kinase domain mutations, 2) identifying druggable targets in the downstream pathways activated by these fusions, and 3) targeting persister cells that contribute to disease recurrence. We utilized the RCAS/tv-a system to establish several mouse models of NTRK1/2/3 fusion-driven gliomas. We found that all analyzed fusions were strong oncogenic drivers on their own, while the loss of additional tumor suppressors (Cdkn2a or Pten) further increased the aggressiveness of these tumors. These mouse models exhibit similar treatment responses as human tumors, initially responding to various TKIs but eventually recurring due to the presence of treatment-resistant persister cells. To mimic the emergence of resistance-associated mutations, we directly introduced different kinase domain mutations into the NTRK fusion sequence or co-expressed secondary mutations (BRAF-V600E or KRAS-G12D). These modifications altered the response to TKI treatment both in vitro and in vivo. Overall, these models serve as valuable tools for studying the biology of NTRK fusion tumors, their treatment response in a treatment-naïve or -experienced state, and the mechanisms underlying treatment resistance.
BIOM-40. THERABIOME-GBM: THERAPEUTIC OUTCOMES RELATED TO GUT MICROBIOME IN GLIOBLASTOMA (GBM) PATIENTS RECEIVING CHEMO-RADIATION: A PROSPECTIVE OBSERVATIONAL STUDY
Authors: Terry Ng, Bader Alshamsan, Thanh Nguyen, James Butcher, Carol Stober, Lisa Vandermeer, Garth Nicholas, Alain Stintzi, Vimoj Nair
Journal: Neuro-Oncology (2023)

Abstract PURPOSE A major barrier to improving outcomes in glioblastoma multiforme (GBM) is overcoming a heavily immunosuppressed tumor and systemic environment, as demonstrated by several negative phase III randomized studies of nivolumab in both newly diagnosed and recurrent GBM. In several mouse avatar and human studies across several tumor cohorts including in a humanized microbiome GBM model, re-establishing a new gut microbiome (GM) via fecal transplantation led to tumor responses to PD-1/PD-L1 inhibition. A recent scoping review confirmed a paucity of GM clinical data of a uniform GBM cohort with adequate longitudinal GM sample collection. We are conducting a single-center prospective observational study to establish the feasibility of collecting stool samples throughout the time course of GBM treatment and upon recurrence, and to understand the gut microbiome dynamics of newly diagnosed IDH-wild type (WT) GBM patients. METHODS Patients with newly diagnosed unifocal IDH-1 R132H WT WHO grade 4 GBM, ECOG 0-2, at least 70% tumor resected with plan to receive temozolomide-radiation (TMZ-RT) and adjuvant TMZ +/- Tumor Treating Fields are eligible. Stool samples will be collected prior to TMZ-RT, 4 weeks after TMZ-RT, after adjuvant TMZ, and upon recurrence. The primary endpoint is feasibility, defined as stool sample obtained pre-RT, post-RT (pre-adjuvant TMZ), and at time of recurrence in ≥ 70% of enrolled participants, 75% of target sample size enrolled within 2 years, and stool sample volume and quality sufficient for analysis in ≥ 75% of collected samples. Secondary endpoints include progression-free survival (PFS) in pre-defined GM subgroups, GM taxonomy and diversity in late vs. early progressors, and GM differences in patients with and without post-RT necrosis. Age, sex, race, concurrent medication, corticosteroid use, and diet will be carefully accounted for. Patient reported outcomes using EORTC-QLQ-BN20 and QLQ-C30 will be collected at baseline, 3-, 6-, 9-, and 12-months.